Cardiovascular diseases are diseases which are leading causes of death in advanced countries. Primary and secondary prevention of this disease is a national health issue of importance, and recently, importance of the primary prevention which prevents the disease before the onset is widely recognized.
Cardiovascular diseases such as coronary artery diseases and cerebral stroke have common pathological background of arteriosclerosis, and risk factors of the arteriosclerosis include smoking, dyslipidemia (hyperlipidemia), hypertension, diabetes, obesity, lack of exercise, and the like. Accordingly, minimization of these risk factors is important in reducing the risk of the onset of cardiovascular diseases.
Accumulated investigations have proven that onset and progress of the arteriosclerosis is induced by the overlapping of a plurality of risk factors. The most important risk factor is dyslipidemia.
According to “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012” (Non-patent literature 1), goals are set for the patients diagnosed with dyslipidemia depending on the control division based on the risk (absolute risk) of suffering from atherosclerotic diseases (namely, coronary artery disease, cerebral stroke, and arteriosclerosis obliterans based on atherosclerosis). More specifically, the control division is set by stratification based on the presence and absence of the additional risk of diabetes, chronic kidney disease, noncardiogenic cerebral infarction, and peripheral arterial disease. According to this guideline, life style is first improved and the adaptation of pharmacotherapy is then considered in the case of the primary prevention (the case with no history of the onset of coronary artery disease), while pharmacotherapy is considered together with the improvement of the life style in the case of the secondary prevention (the case with the history of the onset of the coronary artery disease).
Most typical therapeutic agents for dyslipidemia (in particular, high low density lipoprotein (hereinafter also referred to as “LDL”) cholesterolemia) used for pharmacotherapy are statin drugs (inhibitors for hydroxymethylglutaryl-CoA (hereinafter also referred to as “HMG-CoA”) reductase). The statin drugs which emerged in late 1980's are now sold in more than a hundred countries, and these drugs are said to be administered to at least 30 million people per day. Non-patent literature 1 describes that use of statin drug is recommended for high LDL cholesterolemia, and administration of eicosapentaenoic acid (hereinafter also referred to as “EPA”) is considered in the case of dyslipidemia with high risk of cardiovascular disease as in the case of complication with diabetes or hypertension. The EPA preparation contains high purity ethyl eicosapentaenoate ester (hereinafter also referred to as “EPA-E”) which has been extracted, for example, from sardine oil, esterified, and purified as an effective component, and it has the action of reducing blood neutral fat as well as the action of inhibiting intravascular thrombus formation through suppression of the aggregatory action of the platelet.
Patent Literature 1 describes a composition for preventing recurrence of cardiovascular events containing the EPA-E as an effective component which is useful for the prevention of the recurrence (secondary prevention) of the cardiovascular event, and in particular, which is expected to have a preventive effect for the cardiovascular event that recurs despite the therapy using the HMG-CoA reductase inhibitor and the recurrence of cardiovascular event that takes place after the passage of the unstable period after the cardiovascular reconstruction in the hyperlipidemia patient.
Patent Literature 2 describes a composition for preventing recurrence of cerebral stroke containing the EPA-E as an effective component which is useful in preventing the recurrence (secondary prevention) of the cerebral stroke, and more particularly, which is expected to have a preventive effect for the cerebral stroke that recurs despite the therapy using the HMG-CoA reductase inhibitor and the recurrence of cerebral stroke that takes place after 6 month or more after the onset of the cerebral stroke in the hyperlipidemia patient.
Non-Patent Literature 2 describes that, in the evaluation of the prevention of incipiency (primary prevention) of coronary artery disease for about 5 years, 18% decrease was found for the group of hypercholesterolemia patients having the EPA-E and the statin drug administered, although this result was not significant in terms of the risk compared to the group of patients with single administration of the statin drug.
However, it was not clear whether the EPA preparation was effective as an agent for primary prevention of cardiovascular disease irrespective of the suffering from dyslipidemia and/or the administration of the HMG-CoA reductase inhibitor preparation. Test items and reference values for the administration were also unclear.
In the meanwhile, Non-Patent Literature 3 discloses that ratio of the concentration of EPA to the concentration of arachidonic acid (hereinafter also referred to as “AA”) in the plasma total lipid (hereinafter also referred to as “EPA/AA ratio”) is expected for its use as a new bio-marker for the risk of cardiovascular death based on the results of an epidemiologic study. Non-Patent Literature 4 describes that the value of serum high sensitivity C reactive protein (hereinafter also referred to as “hs-CRP”) is expected for its use as a new bio-marker for the risk of the onset of the cardiovascular disease also based on the results of an epidemiologic study. However, it has been unclear whether appropriate evaluation for the risk of the cardiovascular disease, and in particular, the risk of incipiency (hereinafter also referred to as “primary risk”) of the cardiovascular disease is possible.